Process for the preparation of leukotriene anatgonists

ABSTRACT

The present invention relates to a process for the preparation of a compound of formula (I) or a sodium salt thereof ##STR1## wherein HET is 7-chloroquinolin-2-yl or 6,7-difluoroquinolin-2-yl, which comprises: reacting the dilithium dianion of 1-(mercaptomethyl)cyclopropaneacetic acid with a compound of formula (II) ##STR2## wherein HET is as defined above and L is arylsulfonyl or alkylsulfonyl. The invention further provides the dicyclohexylamine salt of a compound of formula (I).

CROSS REFERENCE

This is a division of application Ser. No. 08/350,428 filed Dec. 9, 1994which is application is a continuation-in-part of U.S. Ser. No.08/174,931 filed Dec. 28, 1993, now abandoned, which is herebyincorporated in its entirety.

BACKGROUND OF THE INVENTION

The leukotrienes constitute a group of locally acting hormones, producedin living systems from arachidonic acid. The major leukotrienes areLeukotriene B4 (abbreviated as LTB4), LTC4, LTD4, and LTE4. Thebiosynthesis of these leukotrienes begins with the action of the enzyme5-lipoxygenase on arachidonic acid to produce the epoxide known asLeukotriene A4 (LTA4), which is converted to the other leukotrienes bysubsequent enzymatic steps. Further details of the biosynthesis as wellas the metabolism of the leukotrienes are to be found in the bookLeukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam(1989). The actions of the leukotrienes in living systems and theircontribution to various disease states are also discussed in the book byRokach.

Recently a number of compounds of formula (1) in which A representsoptionally substituted heterocycle, and pharmaceutically acceptablesalts thereof, have been disclosed as leukotriene antagonists andinhibitors of leukotriene biosynthesis. ##STR3##

EP 480,717 discloses compounds of formula (1) in which A representsoptionally substituted quinoline; more specifically disclosed is thecompound in which A represents 7-chloro-2-quinolinyl. U.S. Pat. No.5,270,324 discloses two compounds of formula (1) in which A represents6-fluoro- or 6,7-difluoro-2-quinolinyl. In co-pending is applicationU.S. Ser. No. 994,869, filed Dec. 22, 1992 (EP Published Application604,114) there is disclosed compounds in which A is halo-substitutedthieno[2,3-b]pyridine, particularly2,3-dichlorothieno[2,3-b]pyridin-5-yl.

The reported syntheses of compounds of formula (1) proceed through theircorresponding methyl esters and involve coupling methyl1-(mercaptomethyl)cyclopropaneacetate with a mesylate exemplified byformula (III), generated in situ. The methyl esters of compounds offormula (I) are hydrolyzed to the free acids and the latter converteddirectly to the corresponding sodium salts. This process is notparticularly suitable for large-scale production because it requirestedious chromatographic purification of the methyl ester intermediatesand/or the final products, and the product yields are low. Furthermore,the final products, as the sodium salts, were obtained as amorphoussolids which are often not ideal for pharmaceutical formulation.

Accordingly, there exists the need for an efficient synthesis ofcompounds of formula (1) which is amenable to scale-up, providesimproved overall product yield, and provides the product sodium salts incrystalline form.

King et al, J. Org. Chem., 1993, 58:3731-3735 reported the synthesis ofL-699,392 via the following sequence: ##STR4##

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparationof compounds of formula (I); to an improved process for the preparationof the precursor 1-(mercaptomethyl)cyclopropane-acetic acid; and tointermediate compounds.

Compounds of formula (I) are leukotriene antagonists and are usefulagents in the treatment of asthma as well as other conditions mediatedby leukotrienes, such as inflammation and allergies.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the X-ray powder diffraction pattern of the compound ofExample 6.

FIG. 2 depicts the X-ray powder diffraction pattern of the compound ofExample 7.

FIG. 3 depicts the X-ray powder diffraction pattern of the compound ofExample 8.

FIG. 4 depicts the X-ray powder diffraction pattern of the compound ofExample 10.

FIG. 5 depicts the X-ray powder diffraction pattern of the compound ofExample 11.

FIG. 6 depicts the X-ray powder diffraction pattern of the compound ofExample 13.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides in one aspect a process for thepreparation of a compound of formula (I) or a sodium salt thereof##STR5## wherein HET is 7-chloroquinolin-2-yl or6,7-difluoroquinolin-2-yl, which comprises: generating the dilithiumdianion of 1-(mercaptomethyl)cyclopropaneacetic acid; reacting saiddianion with a compound of formula (II) ##STR6## wherein HET is asdefined previously and L is arylsulfonyl or alkylsulfonyl. Preferably,HET is 7-chloroquinolin-2-yl, and L is methanesulfonyl. In a preferredembodiment, the process further comprises: converting a compound offormula (I) into the dicyclohexylamine salt; and converting thedicyclohexylamine salt of a compound of formula (I) into thecorresponding sodium salt.

The present invention provides in another aspect the dicyclohexylaminesalt of a compound of formula (I). The dicyclohexylamine salt is readilyisolable in crystalline form and is advantageously used as a means forthe purification of a compound of formula (I), and in the preparation ofcrystalline sodium salt of a compound of formula (I).

Accordingly, another aspect of the invention provides a process for thepreparation of crystalline sodium salt of a compound of formula (I)which comprises: treating the dicyclohexylamine salt of a compoundformula (I) with an acid; treating the product thus obtained with asource of sodium ion; crystallizing the sodium salt of a compound offormula (I). In a preferred embodiment, said acid is acetic acid, andsaid crystallization is effected from toluene/acetonitrile.

The invention also provides the compound1-(mercaptomethyl)cyclopropaneacetic acid, and salts thereof, preferablythe dilithium salt. In yet another aspect of the invention there isprovided a process for the preparation of1-(mercaptomethyl)cyclopropaneacetic acid which comprises: providing asolution of 1-(acetylthiomethyl)cyclopropaneacetonitrile in an organicsolvent; treating said solution with an aqueous solution of a base toform a biphasic phase. In a preferred embodiment, said base is sodiumhydroxide.

Yet another aspect of the invention provides crystallinemethanesulfonates of the formula (III) ##STR7## wherein HET is aspreviously defined under formula (I).

DEFINITIONS

AcS=acetylthio

DCHA=dicyclohexylamine

DMF=dimethylformamide

DSC=differential scanning calorimetry

HOAc=acetic acid

IPAc=isopropyl acetate

MsCl=methanesulfonyl chloride=mesyl chloride

RT=room temperature

THF=tetrahydrofuran

"Arylsulfonyl" means any benzenesulfonyl groups commonly used to converthydroxy to a leaving group, and includes substituted benzenesulfonylsuch as toluenesulfonyl.

"Alkylsulfonyl" means lower alkanesulfonyl having one to four carbonatoms such as methanesulfonyl.

Before describing the invention in detail, the overall reaction sequencein the synthesis of compounds of formula (I) is first briefly discussed.The reaction sequence starting from known materials is illustrated inSchemes 1 to 3. ##STR8##

Scheme 1 depicts the preparation of the thiomethylcyclopropaneaceticacid sidechain precursor. In step (1a), 1,1-cyclopropanedimethanol (IV)is convened to the corresponding cyclic sulfite (V) using thionylchloride and in the presence of a base such as diisopropylethylamine.The reaction is carried out in an inert organic solvent, for examplehalogenated hydrocarbon such as dichloromethane, or aromatic hydrocarbonsuch as toluene. The reaction is essentially complete by the end ofaddition of thionyl chloride.

In step (1b), the cyclic sulfite (V) is treated with a catalytic amountof sodium iodide and sodium cyanide to provide the correspondinghydroxy-nitrile (VI). The reaction is carried out indimethylformamide/toluene or dimethylformamide/isopropyl acetate at atemperature ranging from about 65° to about 90° C. Preferably thereaction temperature is at about 70° C.

In step (1c), the hydroxy-nitrile (VI) is first convened to its mesylateusing methanesulfonyl chloride and in the presence of a tertiary aminebase such as diisopropylethylamine, triethylamine, and the like. Themesylate is then treated with potassium thioacetate to provide1-(acetylthiomethyl)cyclopropaneacetonitrile (VII). Alternatively, themesylate is treated with thiolacetic acid in the presence of a base suchas triethylamine to provide (VII)

In step (1d), 1-(acetylthiomethyl)cyclopropaneacetonitrile (VII) isconverted to 1-(mercaptomethyl)cyclopropaneacetic acid (VIII) in abiphasic solvent system. This step is described in further detail laterin the specification.

The reaction sequence of Scheme 1 may also be carried out according tothe following procedure.

The conversion to the cyclic sulfite (V) may be accomplished by reactingthe diol (IV) with diisopropylsulfite, [(CH₃)₂ CH]₂ SO₃, which in turnis obtained from thionyl chloride and isopropanol. The reaction of thediol and diisopropylsulfite is carried out in an inert organic solventsuch as dimethylformamide/toluene, and in the presence of a catalyticamount of a base such as sodium t-butoxide. The reaction solutionpreferably is dried (to KF<100 μg/mL) prior to addition of the base.Isopropanol produced in the reaction is removed by distillation to drivethe reaction to product formation. Sodium cyanide and catalytic sodiumiodide are added to the cyclic sulfite solution, and the reaction iscarried out at elevated temperature, e.g. at about 70° C., to providethe hydroxy-nitrile compound (VI). The sodium cyanide and sodium iodideare preferably dried prior to use.

The hydroxy-nitrile (VI) in toluene/DMF is convened to the correspondingmesylate as described above. The ratio of toluene:DMF for the mesylationis preferably in excess of 1.9:1; typically, the ratio used is about2.1-2.4:1. Displacement of the mesyl group with thiolacetic acid in thepresence of a base such as triethylamine provides the compound (VII),which is then hydrolyzed as described later to provide the thiol acid(VIII). ##STR9##

Scheme 2 depicts the preparation of the "backbone" portion of compoundsof formula (I). In Scheme 2, R is a lower alkyl group such as methyl andethyl; L is arylsulfonyl or alkylsulfonyl, for example, toluenesulfonylor methanesulfonyl. Preferably, R is methyl and L is methanesulfonyl. Instep (2a) the hydroxy ester (IX) is converted to the diol (X) using aGrignard reagent such as methyl magnesium chloride and in the presenceof cerium chloride. The molar ratio of cerium chloride to methylmagnesium chloride (CeCl₃ :CH₃ MgCl) may be from about 1:1 to about 1:5,and is preferably about 1:4 to about 1:5; the molar ratio of the hydroxyester (IX) and cerium chloride may range from about 1:0.25 to about 1:1,and preferably in the range of about 1:0.5 to about 1:1. The reaction iscarried out under anhydrous conditions, preferably using pre-driedcerium chloride, the hydroxy ester (IX), and solvents. The reaction iscarried out in inert organic solvent such as THF/toluene at temperaturein the range of about -5 to about 5° C. The reaction solution containingthe diol (X) may be concentrated and used in the next step, or the diol(X) may be crystallized from an aromatic solvent such as toluene, and ahydrocarbon solvent such as hexane or heptane, in a ratio of about 1:1to about 1:3.

In step (2b) methanesulfonyl chloride is used to convert the diol (X)into the mesylate (II). This reaction is described in more detailedlater in the specification. ##STR10##

Scheme 3 depicts one aspect of the present invention relating to animproved process for the preparation of a compound of formula (I). Instep 3(a) dilithium salt of 1-(mercaptomethyl)cyclopropaneacetic acid(VIIIa) is coupled with a sulfonate of formula (II). Thus1-(mercaptomethyl)cyclopropaneacetic acid (VIII) is first converted intothe dilithium dianion by contacting the former with a lithium base suchas n-butyl lithium in hexane or heptane, and the like. The reaction iscarried out in an inert organic solvent such as THF, toluene or amixture thereof, and at a temperature of below 0° C., typically at about-5° C. or lower.

The sulfonate (II) is then added to the solution of the dilithiumdianion. The sulfonate may be added directly as a solid, or in ssolution in an inert organic solvent such as THF or toluene, preferablyTHF. Since the sulfonate (II) has limited stability in solution, thesulfonate solution is preferably prepared just prior to addition to thedianion solution, and in any case is best used within about 30 minutes.

The reaction mixture is maintained at below about 0° C, generally atabout -5° C. until completion of the reaction, typically the reaction iscomplete within about 10 hours. The reaction solution containing thedesired product is then treated with a water soluble carboxylic acid,e.g. acetic acid, oxalic acid, tartaric acid and the like to provide thefree acid form of a compound of formula (I); a preferred carboxylic acidis tartaric acid.

In a preferred embodiment, a compound of formula (I) as obtained aboveis converted to the dicyclohexylamine (DCHA) salt. Thusdicyclohexylamine is added to a solution of a compound of formula (I) inethyl acetate, followed by hexanes to effect crystallization of thedicyclohexylamine salt. Preferred ratio of ethyl acetate:hexanes isabout 1:1 to about 1:2. A seed of the dicyclohexylamine salt ispreferably added to the ethyl acetate/hexane solution to acceleratecrystal formation. The dicyclohexylamine salts crystallize as needles.

A second crystalline form of the DCHA salt of a compound of formula (I)may be obtained by crystallization from toluene/heptane. Thus, the freeacid of a compound of formula (I) in an organic solvent such as THF istreated with dicyclohexylamine; toluene is then added and the solutionconcentrated to remove the THF. After dilution with additional toluene,heptane is added to the toluene solution. The ratio of toluene:heptaneis about 2:1 to about 3:1. The crystallization may be accelerated by theaddition of DCHA salt seeds previously obtained from toluene/heptane.

The crystalline DCHA salt of a compound of formula (I) wherein HET is7-chloroquinolin-2-yl obtained from toluene/heptane (Form B) differsfrom the previous form (Form A) obtained from ethyl acetate/hexanes.Form A and Form B exhibit different x-ray powder diffraction pattern asshown in FIGS. 2 and 6, respectively. Form B has been found to be themore thermodynamically stable polymorph because it has a higher meltingpoint and is less soluble than Form A in various solvents at roomtemperature. The differential scanning calorimetry (DSC) curve of FormB, at a heating rate of 10°/min., shows a single melting-decompositionendotherm with an extrapolated onset temperature of approx. 139° C., apeak temperature of 143° C. and an associated heat of approx. 71 J/g.Under the same conditions, the DSC curve of Form A shows a singlemelting-decomposition endotherm with an extrapolated onset temperatureof approx. 117° C., a peak temperature of 124° C. and an associated heatof 61 J/g. At 25° C., the solubility of Form A is 13.5±0.6 mg/ml intoluene and 7.5±0.1 mg/ml in ethyl acetate; the solubility of Form B is18.7±0.2 mg/ml in toluene and 6.6±0.1 mg/ml in ethyl acetate

The readily isolable crystalline dicyclohexylamine salt, in either form,offers a simple and efficient method for the purification of a compoundof formula (I), thereby circumventing the need for tediouschromatographic purification and resulting in higher product yields.

Returning now to the various other aspects of the present invention.Another aspect of the present invention provides a process for thepreparation of crystalline sodium salt of a compound of formula (I) fromthe corresponding dicyclohexylamine salt. Thus, the dicyclohexylaminesalt (Ia) is added to a well agitated mixture of an organic solvent andwater. The organic solvent may be for example an aromatic hydrocarbon,preferably toluene; an ester such as ethyl acetate; an ether such as aTHF; or a mixture thereof, for example toluene/THF. To this suspensionat room temperature is added a water soluble organic acid, for exampleacetic acid, oxalic acid, tartaric acid, and the like; acetic acid ispreferably used. The organic layer containing the free acid is thentreated with a source of sodium ion, for example sodium hydroxide, whichis used in approximately equimolar amount with the free acid.

The solution of the sodium salt in the organic solvent is azeotropicallydried under vacuum and concentrated. Acetonitrile is added at anelevated temperature of about 35° C. to about 45° C., typically at about40° C. To accelerate crystal formation, the solution is seeded withpreviously formed crystals of the sodium salt. Once a good seed bed isestablished (within 2 hours, about 30-90 minutes at 40° C.), moreacetonitrile is added to get a final ratio of acetonitrile:toluene ofabout 2:1 to about 9:1, preferably about 3:1. The crystalline sodiumsalt of a compound of formula (I) is collected after about for 8-12hours at 40° C.

A semi-continuous process for the crystallization of the sodium salt ofa compound of formula (I) has also been developed and is described inthe Examples section.

In another aspect of the invention, there is provided the novel compound1-(mercaptomethyl)cyclopropaneacetic acid (VIII) and salts thereof,preferably the dilithium salt; and a process for the preparationthereof. Compound (VIII) is prepared from1-(acetylthiomethyl)cyclopropaneacetonitrile (VII) by base-catalyzedhydrolysis. It has been found that hydrolysis carried out in waterresults in a significant amount of impurity. The amount of impurity inthe reaction mixture is substantially reduced when the hydrolysis iscarded out in a biphasic system containing an organic solvent and water.In the biphasic hydrolysis the desired intermediate, the thiolate of1-(mercaptomethyl)cyclopropaneacetonitrile, is contained in the aqueouslayer while neutral impurities remain in the organic layer, and are thuseasily removed. In addition, crude (VII) may be used in the biphasichydrolysis thereby avoiding the need to chromatographically purify(VII).

Thus compound (VII) is dissolved in an organic solvent; suitablesolvents are for example aromatic hydrocarbons such as toluene, xylenes,and the like; the preferred solvent is toluene. A solution of compound(VII) in the organic solvent is treated with an aqueous solution of abase, such as sodium hydroxide. The reaction may be carried out at atemperature ranging from room temperature to reflux point of thereaction mixture. The hydrolysis to compound (VIII) is generallycomplete within several days at room temperature, typically about 6days; and several hours at reflux.

Preferably, the biphasic mixture is maintained at room temperature untilthe starting material (VII) has been substantially converted to theintermediate, the sodium thiolate of1-(mercaptomethyl)cyclopropaneacetonitrile, typically about 6 to 18hours. The aqueous solution containing the intermediate is separatedfrom the organic layer containing the unwanted impurities. The aqueoussolution is maintained at elevated temperature up to the reflux point tocomplete the conversion to (VIII), e.g. at 80° C. for about 12 to 16hours.

The solution is then acidified to form (VIII) as the free acid, andextracted with an organic solvent such as toluene or heptane, thenconcentrated. The concentrated solution of (VIII) in toluene is stablefor several months, or compound (VIII) may be crystallized fromhydrocarbon solvents such as hexanes, heptane, pentane and the like toreject some of the impurities present in the starting material (VII).Thus, a mixture of compound (VIII) in heptane is warmed to 34° C. tocompletely solubilize the compound, and allowed to slowly cool to about25° C. Seeding the mixture with crystals of compound (VIII) may be usedto accelerate crystal formation. The mixture is cooled to about -5° C.over about 3 hours for crystal formation.

Another aspect of the present invention provides crystalline mesylatesof the formula (III): ##STR11## wherein HET is as previously definedunder formula (I); preferably HET is 7-chloro-2-quinolinyl.

The mesylate (III) is prepared from the corresponding diol (X). Thereaction is carried out in an inert organic solvent such as toluene, ortoluene and acetonitrile or THF. Other suitable solvents are for exampleDMF or DMF/acetonitrile. The reaction is carried out in the presence ofa tertiary amine base such as diisopropylethylamine, and at atemperature of ≦0° C., preferably at between about -25° C. to about -15°C. The reaction is usually complete within about 5 hrs. The preferredconditions for selective monomesylation at the secondary hydroxy are:toluene:acetonitrile solvent with a preferred ratio of about 1:2 toabout 1:3; reaction temperature range of about -25° C. to about -15° C;and diisopropylethylamine as the base. The mesylate (III) has limitedstability in solution; therefore, it is preferably isolated in solidform which when stored at a temperature of about -15° C. and below, issufficiently stable for six months or more. Crystallization of themesylate (III) is preferably carried out at temperature of 5° C. orbelow from toluene:acetonitrile, preferably at a ratio of about 1:2 toabout 1:3. The isolation of the mesylate (III) renders the coupling withthe thiolacid (VIIIa) feasible as a large-scale production process forcompounds of formula (I).

The following examples are provided to more fully illustrate the presentinvention. The examples are not meant to limit in any manner the scopeof the invention as defined in the claims.

EXAMPLE 1 1,1-Cyclopropanedimethanol Cyclic Sulfite

Method A

To a 1 L round bottom flask equipped with a stirrer, a thermocouple, anitrogen inlet and a syringe pump were placed dichloromethane (645 mL)and 1,1-cyclopropanedimethanol (10.64 g; 97.93 mmol). The mixture wasstirred for 10 minutes to ensure complete dissolution.N,N-Diisopropylethylamine (34.21 mL; 195.86 mmol) was added, and thesolution was cooled to 0°-5° C. Thionyl chloride (7.01 mL; 96.04 mmol)was added subsurface through a teflon needle via a syringe pump over 60minutes. The reaction solution was transferred to a separatory funnelcontaining cold (0°-5° C.) phosphate buffer (pH=7.2, 650 mL). Afterequilibration, the layers were separated. The product solution indichloromethane was washed with 2 wt % sodium chloride solution (650mL), and the product solution was then azeotropically dried andconcentrated at 35°-40° C. under atmospheric pressure to 50 mL. Assayedyield of title compound=13.07 g (90%).

Method B

A 25 mL graduated cylinder equipped with a ground glass joint wascharged with 7.14 mL (97.9 mmol) of thionyl chloride and then dilutedwith toluene to a volume of 21 mL.

To a 1 L round bottom flask equipped with an overhead. stirrer, athermocouple, a nitrogen inlet and a syringe pump were placed toluene(636 mL), 1,1-cyclopropanedimethanol (10.00 g; 97.9 mmol) andN,N-diisopropylethylamine (32.41 mL; 186.1 mmol). The two phase mixturewas vigorously stirred at 22° C. The thionyl chloride:toluene solution(21 mL; 97.9 mmol) was added subsurface through a teflon needle via asyringe pump over 90 minutes maintaining the reaction temperature ≦40°C. After completing the addition of thionyl chloride, the reactionmixture was stirred for another 6-12 hours to ensure max. conversion tothe cyclic sulfite. The reaction mixture was transferred to a separatoryfunnel containing cold (0°14 5° C.) phosphate buffer (pH=7.2, 650 mL).After equilibration, the layers were separated and the product solutionin toluene was washed with 2 wt % sodium chloride solution (650 mL). Theproduct solution was then azeotropically dried and concentrated at40-45° C./70 Torr to 70 mL. Assayed yield of title compound=12.33 g(85%).

EXAMPLE 2 1-Hydroxymethyl)cyclopropaneacetonitrile

Method A

A 250 mL round bottom flask equipped with an overhead stirrer, athermocouple, distillation head and receiving flask was charged with thesolution of the cyclic sulfite of Example 1 in dichloromethane (61 mL;158.9 mg/,mL; 9.69 g). The solution was concentrated to approx. 20 mL bydistillation under atmospheric pressure. Isopropyl acetate (2×30 mL) wasadded to the batch and the distillation was continued to a final volumeof 13 mL. Dimethyl-formamide (21 mL) was added to the solution at >55°C. and the solution was cooled to RT.

A 250 mL round bottom flask equipped with an overhead stirrer, athermocouple, a reflux condenser and a nitrogen inlet was charged with40 mL of the above solution of cyclic sulfite (9.28 g; 62.6 mmol) inDMF:IPAc (4:1). Sodium cyanide (4.61 g; 94 mmol) and sodium iodide (3.75g; 25.0 mmol) were added at RT. The reaction mixture was heated to70°±3° C. and aged at that temperature until the reaction was complete.The reaction mixture was allowed to cool to room temperature and dilutedwith cold (0°-5° C.) isopropyl acetate (187 mL). The dark yellow slurry(218 mL) was transferred to a separatory funnel containing cold (0°-5°C.) 1.0M sodium hydroxide (107 mL). After equilibration, the layers wereseparated. The organic layer was s washed with brine (53 mL). Theaqueous layer was back-extracted with cold (0°-5° C.) isopropyl acetate(107 mL), and the organic layer washed with brine (27 mL). The twoorganic layers were combined to provide 17.5 mg/ml of the titledcompound in solution. Assayed yield of title compound=5.03 g; 72.2%.

Method B

A 12 L 3 neck round bottom flask equipped with an overhead stirrer, athermocouple, a distillation head and 3 L receiving flask was chargedwith the solution of the cyclic sulfite of Example 1 in dichloromethane(2.0 L; 174.0 g/L; 343.6 g). The solution was concentrated and a secondportion of the cyclic sulfite in dichloromethane (2.0 L; 155.9 g/L;311.8 g) was added and further concentrated to approx. 2.3 L bydistillation under atmospheric pressure. Toluene (1.7 L) was added tothe batch and the distillation was continued to a final volume ofapprox. 1.7 L. Dimethylformamide (1.81 L) was added to the solution andconcentration was continued under vacuum (approx. 105 Torr).

A 12 L 3 neck flask equipped with an overhead stirrer, a thermocouple, adistillation head and a nitrogen inlet which contained 2.2 L of theabove solution of cyclic sulfite (655.3, 4.40 mol) in DMF:toluene(97:3/v:v) at room temperature was charged with sodium cyanide (218.9 g;4.40 mol) and sodium iodide (131.9 g; 0.88 mol). The reaction mixturewas heated to 70°±3° C. over a 1 h period and aged at that temperatureuntil the reaction was complete.

The reaction mixture was slowly diluted with 6.6 L of toluenemaintaining the temperature of the batch at approx. 70° C. The hazyamber solution was charged with 80 mL of water over a 30 min period. Thereaction mixture was cooled to 27° C. and the reaction flask wasequipped with a 2 L dropping funnel which contained 2 L of toluene. Thereaction mixture was concentrated under vacuum while the toluene wasadded from the dropping funnel. The reaction mixture was cooledovernight and then filtered through a medium porous sintered glassfunnel (3 L); the cake was then flushed with an additional 2.2 L oftoluene. The yield of the title compound was 87.5%.

EXAMPLE 3 1-(Acetylthiomethyl)cyclopropaneacetonitrile

Method A

A 500 mL round bottom flask equipped with an overhead stirrer, athermocouple, distillation head and receiving flask was charged with thesolution of the hydroxy-nitrile of Example 2 in isopropyl acetate andDMF (118 mL; 91 mg/mL; 10.74 g). The solution was concentrated toapprox. 50 mL by distillation under atmospheric pressure. Isopropylacetate (200 mL) was added to the batch and the distillation wascontinued to a final volume of 154 mL.

The distillation set up was replaced with an addition funnel. Thesolution was cooled to -3°±2° C. and triethylamine (17.4 mL) was addedover 1 minute. Mesyl chloride (8.93 mL) was added slowly from theaddition funnel keeping the temperature of the batch below 0° C. Theaddition took 30 minutes. The reaction mixture (approx. 180 mL) wastransferred to a separatory funnel containing cold (0°-5° C.) water (76mL). After equilibration, the layers were separated and the organiclayer was washed with brine (76 mL).

The solution of 1-(methanesulfonyloxymethyl)cyclo-propane-acetonitrilewas transferred to a 500 mL round bottom flask equipped with an overheadstirrer, a thermocouple and a nitrogen inlet. Solid potassiumthioacetate (14.28 g) was added to the solution at 0° C. Theheterogeneous mixture was warmed to 20°±2° C. and aged for 16 to 18hours. Water (76 mL) was added to the reaction mixture and the contentsof the reaction flask were transferred to a separatory funnel. Thelayers were separated and the organic layer was washed with brine (76mL). The solution of the title compound in isopropyl acetate wasconcentrated under vacuum (75 Torr, 50° C.) to a volume of approx. 50mL. Toluene (3×75 mL) was added and the concentration was continuedunder vacuum (60 Torr, 50° C.) until <1% of isopropyl acetate remained.Assayed yield of title compound=13.12 g (81%).

Method B.

A solution of 1-(hydroxymethyl)cyclopropaneacetonitrile (34.2 g, 0.308mol) in toluene:DMF (1.9:1,210 mL) and triethylamine (49.4 mL, 0.354mol) were combined in a 3-neck, 1L round bottom flask equipped withmechanical stirring and a thermocouple, flushed with nitrogen and cooledto -15° C. Mesyl chloride (26 mL) was added dropwise over 0.5 hr.,keeping the temperature below 5° C. Ethanol (77 mL), triethylamine (86mL, 0.616 mol) and thiolacetic acid (26.4 mL) were added sequentially asquickly as possible. The mixture was removed from the cooling bath andheated to 35° C. This temperature was maintained until <1% mesylateremains, about 7 hrs. Water (250 mL) was added and the mixture wasshaken. The phases were separated, the aqueous phase was back-extractedwith toluene (200 mL), and the organic phases were combined to providethe title compound (48.3 g at 103 mg/mL, 93% yield, purity: 91 area %).

EXAMPLE 4 1-(Mercaptomethyl)cyclopropaneacetic acid

A 1 liter round bottom flask equipped with an overhead stirrer, athermocouple, distillation head and receiving flask was charged with thesolution of 1-(acetylthiomethyl)cyclopropane-acetonitrile in toluene(248.2 mL; 16.93 g; 100.0 mmol). The solution was concentrated undervacuum (75 Torr, 50° C.) to a volume of approx. 100 mL. The distillationset up was removed, the solution was cooled under nitrogen to 20°-25°C., and aqueous 5N sodium hydroxide (100 mL; 500 mmol) was added. Thebiphasic mixture was vigorously agitated at 20°-25° C. for 16-18 hours.

The aqueous layer was transferred to a 250 mL flask equipped with anoverhead stirrer, a thermocouple, a nitrogen inlet and a refluxcondenser. The solution was refluxed for approx. 2 hours, cooled to0°-5° C. and 8N hydrochloric acid (62.5 mL; 500 mmol) was added toadjust the pH of the aqueous medium to 2.0. Toluene (190 mL) was addedto the aqueous slurry with good stirring. The biphasic mixture wastransferred to a separatory funnel and the layers were separated.Toluene (100 mL) was added to the aqueous layer and the layers wereseparated. The two organic layers were combined and concentrated undervacuum (60 Torr, 50° C.) to 82 mL, and the concentrated solution wasfiltered. Assayed yield of title compound=11.99 g (82%). The solution ofthe title compound in toluene was stored under nitrogen.

A 250 mL round bottom flask equipped with an overhead stirrer, athermocouple, distillation head and receiving flask was charged with thesolution of the title compound in toluene (100 mL; 11.50 g; 78.66 mmol).The solution was concentrated under vacuum (45 Torr, ≦40° C.) to avolume of approx. 23 mL. Hexane (92 mL) was added to the solution at20°±2° C., and the solution was seeded with 10 mg of the title compound.The mixture was aged at 20°±2° C. for approx. 2 hrs to obtain a goodseed bed. A sample of the slurry was examined by cross-polarizedmicroscopy to confirm crystallinity of the solid.

The slurry was cooled to 0° to -5° C. and aged for about 2 hours, thenallowed to warm to 20°±2° C. and aged overnight to digest the finecrystals. The slurry was cooled to -20°±5° C. over 3 hours and aged forone hour. A sample of the slurry was examined by cross-polarizedmicroscopy to confirm crystallinity of the solid. The slurry wasfiltered and the cake was washed with cold (20°±5° C.) hexanes (25 mL),then dried under suction under nitrogen at 20°±2° C.

¹ H NMR (CDCl₃) δ11.8 (bs, 1H), 2.64 (d, 2H), 2.52 (s, 2H), 1.36 (t,1H), 0.64-0.52 (m, 4H).

DSC melting endotherm with a peak temperature of 49° C. and anassociated heat of 122 J/g.

X-ray powder diffraction*-crystallinity.

*X-ray powder diffraction patterns in this and subsequent Examples wereobtained with APD3720 (Philips) instrument at ambient temperature andunder N₂.

EXAMPLE 52-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol

Step 1:

In a 5 L flask fitted with mechanical stirrer and distillation head, asuspension of methyl2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)benzoatehydrate (EP 480,717, Example 146, Step 2) (300 g, 0.63 mol) in toluene(3250 mL) was heated to reflux. All solids dissolved to afford ayellow-orange solution. Toluene-H₂ O azeotrope (250 mL) was removed bydistillation at atmospheric pressure (temp. 84°-110° C., T=110° C. afterapprox. 200 mL was removed). The clear solution was cooled to 20° C.KF=76 μg/mL.

Step 2:

A 3-neck 12 L flask fitted with a mechanical stirrer and refluxcondenser was charged with THF (2 L, anhyd.) and CeCl₃ (160 g, 0.65 mol,anhyd.). The gray suspension was heated at reflux for 3-5 hours, thenthe ivory white suspension was cooled to 0° C. A solution of MeMgCl₁ (3Min THF, 1100 mL, 3.30 mol) was added dropwise over 30 min to the CeCl₃suspension, keeping T=0°±5° C. The solution was aged at 0° C. for 2hours. The solution of hydroxy-ester in toluene obtained in is Step 1was added dropwise over 1.5 h keeping -1≦T≦5° C. The solution was agedfor 0.5 h after addition was complete. The reaction was then quenched bycautious addition to 1:12M HOAc/toluene (5 L ea) keeping T≦25° C. Thepale yellow solution was stirred at 20°-25° C. for 10 min, then thelayers were separated. The organic layer was washed with 1×5 L 10% Na₂CO₃ followed by 1×5 L H₂ O. The organic layer (33 mg/mL of the titlecompound) was concentrated by distillation in vacuo (100 mbar, 40° C.)to afford a yellow solution of the title compound (approx. 180-190mg/mL).

Step 3.

A crude solution of the title compound (the diol) in THF/toluene wasconcentrated from a 23.5 mg diol/mL solution to 253 mg diol/mL bydistillation at atmospheric pressure (T=84°-110° C.). The solutiontemperature was then lowered to and maintained at 50° C. Seeding at 50°C. resulted in solution of the diol seed. Hexanes (50 mL) were addeddropwise over 1 hour and then the reaction was seeded again. Once again,the seed appeared to dissolve. An additional aliquot of hexanes (25 mL)was added in a dropwise manner over 15 minutes, at which point whitesolids began to appear in the crystallization vessel. Thecrystallization was aged for 10 minutes followed by the addition ofhexanes (85 mL) over 30 min. The crystallization was aged at 50° C. for30 minutes followed by the addition of hexanes (160 mL) in one portion.Following a 30 minute age, the reaction mixture was cooled to 25° C.over 60 min., and filtered. The title compound was isolated in 89 yield(99.0 analytical %, 99.6 wt % purity).

EXAMPLE 62-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol

A 100 L round bottom flask fitted with a mechanical stirrer,thermocouple, and addition funnel was purged with N₂. The flask wascharged with a solution of the diol in toluene (product of Example 5,17.7 L, 348.5 g/L), CH₃ CN (45.4 L), and diisopropylethylamine (2720mL). The solution was cooled to T=-25°±3° C. in a CO₂ /methanol bath.Methanesulfonyl chloride (1140 mL) was added dropwise over 2.5 h,keeping the T=-25°±2° C. After the addition of mesyl chloride thereaction mixture was seeded with granular seed of the title compound(5.0 g) and aged at -25° C. for 2 hours to afford a thin slurry (largecubic crystals by microscopy; supernatant assay: 21 g/L mesylate;subsequent experiment yielded needle crystals). The temperature wasreduced to -35° C. over 1 hour and then aged for 1 hour (supernatantassay: 14 g/L mesylate). The product was isolated by filtration of thecold suspension under a blanket of N₂. The filter cake was washed withcold CH₃ CN (14 L, -30° C.), followed by a cold hexane wash (16 L, 5°C.). After the washes, the cake was dried on the filter by pulling N₂through the cake at 5° C. for 20 hours. The cake was packaged at 5° C.in double polypropylene bags in a fiber drum and stored at -18° C. toafford the product as a pale yellow solid (5844 g corrected for wt %purity, 81% yield).

¹ H NMR (CDCl₃) δ8.11 (m, 2H), 7.69 (m, 5H), 7.41 (m, 5H), 7.19 (m, 3H),5.70 (dd, 1H), 3.25 (m, 1H), 3.04 (m, 1H), 2.76 (s, 3H), 2.45 (m, 1H),1.92 (s 1H), 1.65 (s, 6H).

X-ray diffraction pattern: as shown in FIG. 1. needle form instead ofcubic.

EXAMPLE 71-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropaneaceticacid dicyclohexylamine salt

Step 1:

To a 100 L reactor equipped with a mechanical stirrer, a thermocouple, anitrogen inlet and an addition funnel were placed tetrahydrofuran (33 L)and 1-(mercaptomethyl)cyclopropaneacetic acid (1.317 kg, 7.938 mol). Themixture was stirred for 10 minutes to ensure complete dissolution. Aclear, pale yellow solution resulted. The solution was cooled to -15°±2°C. and n-butyl lithium (1.56M in hexanes, 10.5 L, 16.38 mol) was addedover 75 minutes, maintaining the temperature of the reaction mixture<-5° C. The slurry was aged at -5°±2° C. for 30 minutes.

Step 2:

To a 50 L flask equipped with a stirrer, a thermocouple and a nitrogeninlet was placed tetrahydrofuran (20 L). The solvent was cooled to 0°-5°C. The mesylate of Example 6 (4.501 kg, 7.558 mol) was added via apowder funnel and tetrahydrofuran (2.5 L) was used to rinse the funnel.The mixture was stirred for 15 minutes to ensure complete dissolution. Aclear, pale yellow solution resulted.

Step 3:

The solution of the mesylate from Step 2 was transferred using a 0.25"o.d. polypropylene tubing under nitrogen pressure to the dianion slurryof Step 1 at -5°±2° C. over 75 minutes. The reaction solution was agedat -5°±2° C. for 8.5 hours. The reaction was quenched by pouring theclear, yellow reaction solution into a mixture of ethyl acetate (55 L)and 10% sodium chloride solution (55 L). The mixture was agitated forabout 30 minutes and then the layers were allowed to separate. Two clearlayers were obtained. The aqueous waste layer was drained off. Theorganic product layer was washed with 0.5M tartaric acid (36 L), thentwice with water (36 L each time). The product solution was concentratedunder vacuum to approx. 10 L. The product was dissolved in ethyl acetate(44 L) and the solution was allowed to equilibrate to room temperature(20°±2° C.).

Step 4:

To the solution of the free acid in ethyl acetate (54 L) in 2×100 L,3necked flask equipped with a mechanical stirrer, a thermocouple, anitrogen inlet and an addition funnel was added dicyclohexylamine (1.8L). The clear solution was seeded with the dicyclohexylamine salt of thetitle compound (14 g). The resulting mixture was aged for about an hour,by which time a thick slurry resulted. A sample of the slurry wasexamined by cross-polarized microscopy to confirm crystallinity of thesolid. Hexane (108 L) was slowly added over 2 hours maintaining a goodagitation of the slurry. The slurry was aged at 20°±2° C. overnight. Asample of the slurry was examined by cross-polarized microscopy toconfirm crystallinity of the solid. The slurry was suction filtered andthe cake washed with cold (0°±2° C.) 1:2 ethyl acetate:hexanes (32 L).The product was dried under vacuum at 40°±2° C. with a nitrogen purge.

Isolated yield=4.745 kg (99 A %; 96 wt %; >99.8% ee; 79% yield).

¹ H NMR (CD₃ OD) δ8.25 (d, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7.83 (d,1H), 7.77 (d, 1H), 7.70 (bs, 1H), 7.54 (d, 1H), 7.49 (d, 1H), 7.46-7.35(m, 4H), 7.12-7.03 (m, 3H), 4.87 (s, active H), 4.03 (dd, 1H), 3.11-3.05(m, 3H), 2.84-2.81 (m, 1H), 2.64 (d, 1H), 2.52 (d, 1H), 2.38 (d, 1H),2.29 (d, 1H), 2.23 (m, 1H), 2.00 (m, 4H), 1.82 (m, 4H), 1.66 (m, 2H),1.51 (two s, 6H), 1.37-1.14 (m, 10H), 0.53- 0.32 (m, 4H).

X-ray powder diffraction pattern: as shown in FIG. 2.

EXAMPLE 8 Sodium1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetate

Toluene (1000 mL) and water ((950 mL) were placed in a 12 literextractor equipped with an overhead stirrer, a thermocouple, a nitrogeninlet and an addition funnel. With good mixing of the solvents, soliddicyclohexylamine salt of Example 7 (64.3 g, 82.16 mmol) was added via apowder funnel and toluene (260 mL) was used to rinse in the remainingsolid. To the well stirred suspension, acetic acid (2M, 62 mL, 124 mmol)was added at room temperature. After approximately 10 minutes stirringwas stopped. Two clear phases (yellow organic layer and colorlessaqueous layer) resulted, and the aqueous waste layer was drained off.Water (950 mL) was charged to the extractor and the layers were mixedthoroughly for approx. 10 minutes. The agitation was stopped and theaqueous waste layer was drained off.

To the organic layer (1270 mL) containing the free acid a titratedsolution of sodium hydroxide in 1% aqueous ethanol (aqueous withoutethanol (0.486M, 169 mL, 82.13 mmol) was added in a steady stream over10 minutes at room temperature under a nitrogen atmosphere. After 10minutes age, the clear solution of the desired sodium salt was filteredthrough a pad of solkafloc using toluene (100 ml) for transfer and cakewash.

The clear tiltrate was transferred under nitrogen to a 3 liter, 3-neckedflask equipped with an overhead stirrer, a thermocouple, a nitrogeninlet and a distillation head. The solution was concentrated undervacuum to about 400 ml (ca. 40 mm Hg, ≦40° C.). The distillation headwas replaced with a reflux condenser and an addition funnel. Theconcentrate was maintained at 40°±2° C. and acetonitrile (400 mL) wasadded over 20 minutes. The clear solution was seeded with 0.5 g of thecrystalline sodium salt, and the resulting mixture was maintained at40°±2° C. for 1.5 hours, by which time a good seed bed was established.

Acetonitrile (400 ml) was slowly added over 20 minutes, maintaining thebatch temperature at 40°±2° C. The white suspension was stirred at40°±2° C. for 1 hour and acetonitrile (400 mL) was slowly added over 20minutes. The slurry was aged at 40°±2° C. for 12 hours. A sample of thesuspension was examined by cross-polarized microscopy to confirmcrystallinity of the solid. The suspension was cooled to RT and aged atRT for 1 hour. The crystalline sodium salt was suction filtered througha sintered funnel under nitrogen. The cake was washed with acetonitrile(400 ml). The crystalline sodium salt cake was broken up in a nitrogenglove bag and dried under vacuum with nitrogen bleed at 40-45° C. Theproduct (49 g, 80.59 mmol, 98% yield) was packaged in a well sealedbrown bottle under nitrogen. The reaction mixture and the isolatedproduct were protected from light at all times.

HPLC assay of the sodium salt: >99.5 A %. Chiral purity: 99.8% ee.

¹ H NMR (CD₃ OD) δ8.23 (d, 1H), 7.95 (d, 1H), 7.83 (d, 1H), 7.82 (d,1H), 7.75 (d, H), 7.70 (bs, 1H), 7.54 (dt, 1H), 7.46 (dd, 1H), 7.42-7.35(m, 3H), 7.37 (d, 1H), 7.14-7.00 (m, 3H), 4.86 (s, active H), 4.03 (dd,1H), 3.09 (m, 1H), 2.82 (m, 1H), 2.66 (d, 1H), 2.52 (d, 1H), 2.40 (d,1H), 2.30 (d, 1H), 2.24-2.14 (m, 2H), 1.51 (two s, 6H), 0.52-0.32 (m,4H).

DSC melting endotherm with a peak temperature of 133° C. and anassociated heat of 25 J/g.

X-ray powder diffraction pattern: as shown in FIG. 3.

EXAMPLE 92-(2-(3(S)-(3-(2-(6,7-difluoro-2-quinolinyl)-ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol

The general procedures described in Examples 5 and 6 were followedexcept methyl2-(2-(3(S)-(3-(2-(6,7-difluoro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)benzoatewas used, in Example 5, Step 1, about 750 mL to about 1 L of thetoluene-H₂ O azeotrope was removed, and in Example 6 DMF:acetonitrile(3: 1) was used as the solvents to provide the title compound.

EXAMPLE 101-(((1(R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropaneaceticacid dicyclohexylamine salt

The general procedure of Example 7 was followed except the compound ofExample 9 was used to provide the title compound. DSC melting endothermwith a peak temperature of 132° C. X-ray powder diffraction pattern: asshown in FIG. 4.

EXAMPLE 11 Sodium1-(((1(R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropaneacetate

The general procedure of Example 8 was followed except the compound ofExample 10 was used to provide the title compound. DSC endotherm with apeak temperature of 119° C. X-ray powder diffraction pattern: as shownin FIG. 5.

EXAMPLE 12 Alternative method for the preparation of1-(mercaptomethyl)cyclopropaneacetic acid

Step 1:

Diisopropyl sulfite

Toluene (500 mL) and isopropanol (306 mL, 4 mole) were combined undernitrogen in a 2L flask equipped with a dropping funnel and thermocouple.Thionyl chloride (73 mL, 1 mole) was added from the dropping funnel over30 minutes maintaining the temperature at 15°-25° C. When the additionwas complete, the reaction mixture was put under vacuum to remove HCl.Vigorous HCl evolution was noted at 150 mm.

The pressure was lowered slowly. When gas evolution ceased, the mixturewas concentrated to remove toluene and excess isopropanol. Concentrationwas continued until less than 1% isopropanol remained. Yield=159 g, 95%.Triethylamine (1 mL) was added to stabilize the product and theincipient precipitate was filtered away. The solution was used as is.

Step 2:

1-(Hydroxymethyl)cyclopropaneacetonitrile

Dimethylformamide (225 mL) and 1,1-cyclopropanedimethanol (26.6 g; at 95wt %, actual amount=25.5 g, 250 mmol) were placed in a 1L flask equippedwith a vacuum distillation apparatus. DMF (25 ml) was distilled at 75°C./50 torr, and to the remaining solution was added a solution ofdiisopropyl sulfite in toluene (81.6 mL, 49.9 g, 300 mmol). Toluene (50mL) was distilled at 52° C./55 torr, and the resulting solution had a KFof 98 μg/mL.

Sodium t-butoxide, (2M in tetrahydrofuran, 2.0 mL) was added, anddistillation was begun again at 45° C./50 torr, with 30 mL of distillatecollected. Distillation was continued to collect 60 mL at 50°-70° C./50torr. Sodium t-butoxide (1.0 mL) was added and the distillation wascontinued to collect 60 mL of distillate at 60°-75° C./50 torr. Afterthe addition of more sodium tobutoxide (0.5 mL), and distillation of 30mL at 70-75° C./50 torr, the distillation was stopped, and the mixturewas maintained at 70° C. for 1 h and then cooled to room temperature.The yield of 1,1-cyclopropanedimethanol cyclic sulfite=33.0 g, 89%).

Sodium cyanide (13.5 g, 275 mmol) and sodium iodide (7.5 g, 50 mmol)were added to the solution obtained above, and the heterogeneous mixturewas slowly warmed over 1 h to 70° C., and aged for about 40 h withvigorous stirring. Toluene (400 mL) was added slowly at 70° C., and thenwater (6 mL) was added dropwise over 30 minutes. The mixture was thendried by vacuum distilling 100 mL of toluene; when the KF of the mixturewas 200 μg/mL, it was cooled to 10° C. and filtered. The precipitate waswashed with toluene (100 mL), and the combined tiltrate contained 21.4 gof the title compound (77% from 1,1-cyclopropyldimethanol).

Step 3:

1 -(Acetylthiomethyl)cyclopropaneacetonitrile

The product of Step 2 in toluene/DMF (1.9:1 ) (210 mL for 34.2 g of theproduct compound) and triethylamine (49.4 mL, 0.354 mol) were combinedin a 3-neck 1L round bottom flask equipped with mechanical stirring anda thermocouple, flushed with nitrogen and cooled to -15° C. Mesylchloride (26 mL, 0.339 mmol) was added dropwise over 0.5 h, keeping thetemperature below ±5° C.

Triethylamine (86 mL, 0.616 mmol) and thiolacetic acid (26.4 mL, 0.40mole) were added sequentially as quickly as possible; the mixture wasremoved from the cooling bath and heated to 35° C. This temperature wasmaintained until >1% of the mesylate remained (about 7 h). Water (250mL) was added, the mixture was shaken, and the two phases wereseparated. The aqueous phase was extracted with toluene (200 mL), andthe organic phases were combined. The combined organic phases (470 mL)contained 48.3 g (93%) of the desired product.

Step 4:

1-(Mercaptomethyl)cyclopropaneacetic acid

The product solution of Step 3 (447 g containing 48 g of the productcompound) was washed with deionized water (2×150 mL). In a 1L three-neckflask equipped with nitrogen inlet and mechanical stirring, the organiclayer was deoxygenated. Deoxygenated 5N NaOH (284 mL) was added. Themixture was vigorously stirred at ambient temperature for 6-10 h until2% starting material remained. The aqueous layer was separated andheated at 80° C. for 12-16 h until none of the intermediate1-(mercaptomethyl)cyclopropaneacetamide remained.

The reaction was cooled to 25-30° C. and 930 mL of deoxygenated heptanewas added. The mixture was acidified to pH 3.5-4.0 with 5M NaHSO₄solution over 1 h with stirring and allowed to warm to 30° C. The layerswere separated at 30° C. and the aqueous layer was backextracted with310 mL heptane. The combined organic layers were concentrated to 180 mL.

The mixture was warmed to 34° C. to completely solubilize the productand then allowed to slowly cool to 25° C. over 1 h. The mixture wasseeded at 30° C. After stirring at 25° C. for 1 h to ensure a good seedbed, the mixture was cooled to -5° C. over 3 h. After stirring at -5° C.for 30 minutes, the mixture was filtered and washed with 20 mL of coldheptane. The title compound was obtained as an off-white crystallinesolid (34.3 g, 83%).

EXAMPLE 131-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid dicyclohexylamine salt crystallized from toluene/heptane

Step 1:

To a 2.0 L reactor equipped with a mechanical stirrer, a thermocouple, anitrogen inlet and an addition funnel were placed tetrahydrofuran (132ml) and 1-(mercaptomethyl)cyclopropaneacetic acid (9.830 g, 65.98 mmol).The mixture was stirred for 10 minutes to ensure complete dissolution. Aclear, pale yellow solution resulted.

The solution was cooled to -15°±2° C. n-Butyl lithium (1.70M in hexanes,79.6 ml, 135.26 mmol) was added over 30 minutes, maintaining thetemperature of the reaction mixture <-5° C. The slurry was aged at-5°±2° C. for 30 minutes.

Step 2:

To a 250 ml flask, equipped with a stirrer, a thermocouple and anitrogen inlet were placed mesylate of Example 6 (36.52 g, 62.68 mmol)and THF (106 ml). The solution was cooled to 0°-5° C. The mixture wasstirred for 15 minutes to ensure complete dissolution. A clear, paleyellow solution resulted.

Step 3:

The solution of the mesylate of Step 2 was transferred via cannula tothe dianion slurry of Step 1 at -5°±2° C. over 5 minutes. The reactionsolution was aged at 0°±2° C. for 15 hours. The heterogeneous, yellowreaction solution was quenched by addition to a solution of 10% brine(200 ml). The mixture was agitated for about 10 minutes and the layerswere allowed to separate. The organic product layer was washed with 0.5Mtartaric acid (280 ml), then washed with water (2×120 ml).

The product solution was transferred to a 500 ml 1-neck flask. To thissolution 250 ml of toluene was added along with s dicyclohexylamine(14.44 ml, 72.60 mmol). This clear solution was treated with Darco G-60(1.8 g) and the mixture was stirred under nitrogen for an hour. Themixture was filtered through a bed of solka floc (12 g) using toluene(20 mL) for rinse and transfer. The filtrate and wash were combined andconcentrated under vacuum to ˜200 ml. Another 200 ml of toluene was thenadded and the volume was reduced to 200 ml again.

The above solution was diluted to 640 ml with toluene and transferred toa 2.0 L, 3-necked flask equipped with a mechanical stirrer, athermocouple, a nitrogen inlet, and an addition funnel. The clearsolution was seeded with dicyclohexylamine salt of the title compound(200 mg) previously crystallized from toluene/heptane. The resultingmixture was aged for about 3 hours, by which time a thick slurryresulted. A sample of the slurry was examined by cross-polarizedmicroscopy to confirm crystallinity of the solid. Heptane (280 ml) wasslowly added over 2 hours maintaining a good agitation of the slurry.The slurry was aged at 20°±2° C. overnight. A sample of the slurry wasexamined by cross-polarized microscopy to confirm crystallinity of thesolid. The slurry was suction filtered and the cake washed with 1:1heptane:toluene (200 ml). The product was dried under vacuum at 40°±2°C. with a nitrogen purge. Isolated yield of the title dicyclohexylaminesalt=40.39 g (purity: 99.3 A %, >99.8% ee; 80.6% yield).

In case the purity of the product is below about 99%, the product may befurther purified by swishing with toluene/heptane. For example, the DCHAsalt (98.6A % purity, 10.03 g) was swished with toluene/heptane (1.5:1,300 ml) at room temperature for 5 hours. The slurry was filtered anddried as earlier to obtain further purified DCHA salt (9.63 g, 99.4 A%).

X-ray powder diffraction pattern: as shown in FIG. 6.

EXAMPLE 14 Alternative method for the preparation of sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneace

To a 1L round bottom, 3 neck flask equipped with overhead stirrer andnitrogen bubbler were charged 285 ml of toluene, 85 ml THF, and 215 mldeionized water. To this was charged 25.0 grams of solid DCHA salt of1-(((1-(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid (97.3 wt % purity). To the resulting slurry was charged 23.3 ml of2.04M aqueous acetic acid.

The flask was purged 3 times with nitrogen and vacuum and left with anitrogen blanket. The two phase mixture was agitated for 15 minutes. Theagitation was stopped and the mixture was transferred to a 1000 mlseparatory funnel, the batch was settled for 15 minutes, and the aqueouslayer was cut off.

The organic layer was washed with deionized water (2×215 mL) as above,and the organic layer was returned to a 1L round bottom flask and purged3 times with nitrogen and vacuum. A 0.500M solution of NaOH in 1%aqueous ethanol (63.3 mL) was added to the organic layer. At the end ofthe addition one clear phase was present. The resulting solution wasfiltered through a 0.45 μm nylon membrane filter (precoated with 2.5 gof Solka Floc) into a second 1L round bottom flask. The funnel wasrinsed with 50 ml of toluene which was combined with the initialtiltrate. The resulting solution was vacuum distilled (T≦40° C.) to avolume of ˜165 ml. Toluene (165 ml, 0.45 μm filtered) was added and thesolution concentrated to 165 ml. The toluene dilution/concentration stepwas repeated to provide a solution of 165 ml final volume.

A slurry seedbed was prepared in a 1 liter resin kettle equipped withoverhead stirrer and nitrogen bubbler. To the resin kettle were charged32 ml of 0.45 μm filtered toluene, 64 ml of 0.45 μm filteredacetonitrile, and 3.86 g of title sodium salt seed.

The sodium salt concentrate (165 ml) and sieve dried, 0.45 μm filteredacetonitrile (330 ml, KF<100 μg/ml) were charged simultaneously to theseedbed over 8 hours via two syringe pumps. The seedbed temperature wasmaintained at 20° C. during the addition, and the flowrates were matchedin order to maintain the crystallizer solvent ratio at ˜2:1acetonitrile:toluene. The microscopic appearance of the slurry and thesupernatant concentration were monitored throughout the simultaneousaddition. After the completion of the addition, the resulting slurry wasaged overnight at 20° C. (16 hours).

The crystallized slurry was vacuum filtered under nitrogen insertion,leaving behind ˜100 ml of slurry to serve as the seedbed for asubsequent crystallization. The filtered cake was washed with 238 ml ofsieve dried, 0.45 μm filtered acetonitrile (KF<100 μg/ml). The resultingcake was dried in a vacuum oven at 40°-45° C. for 48 hours. A total of17.75 g of sodium salt were recovered (99.3 wt %).

A second sodium salt formation and crystallization cycle was performedthe same as described above, using the seedbed left from cycle #1. Afterthe completion of the cycle #2 crystallization, the entire slurry wasfiltered without leaving behind a seedbed. The total product isolatedfrom cycle #2 was 20.38 g (99.7 wt %). The overall material balance forthe two cycles was 95.2%, with a yield of 92.1% (corrected for samplingthe mechanical losses due to holdup in the crystallizer).

What is claimed is:
 1. A process for the preparation of a compound offormula (I) or a sodium salt thereof ##STR12## wherein HET is7-chloroquinolin-2-yl or 6,7-difluoroquinolin-2-yl, whichcomprises:generating the dilithium dianion of1-(mercaptomethyl)cyclo-propaneacetic acid; reacting said dianion with acompound of formula (II) ##STR13## wherein HET is as defined above and Lis arylsulfonyl or alkylsulfonyl.
 2. A process according to claim 1which further comprises: converting said compound of formula (I) in freeacid form to the dicyclohexylamine salt.
 3. A process according to claim1 wherein HET is 7-chloroquinolin-2-yl, and L is methanesulfonyl.
 4. Aprocess according to claim 2 wherein HET is 7-chloroquinolin-2-yl, and Lis methanesulfonyl.
 5. A process for the preparation of the crystallinesodium salt of a compound of formula (I) ##STR14## wherein HET is7-chloroquinolino-2-yl or 6,7-difluoroquinolin-2-yl, whichcomprises:treating the dicyclohexylamine salt of a compound of formula(I) with an acid; treating the product thus obtained with a source ofsodium ion; and crystallizing the sodium salt.
 6. A process of claim 5wherein HET is 7-chloro-quinolin-2-yl.
 7. A process of claim 6 whereinthe crystallizing solvent is toluene:acetonitrile.